• Anti-HIV seroconversion [ Time Frame: At 36 months ] [ Designated as safety issue: Yes ]
  
• Safety endpoints, including Grade 1 or higher creatinine toxicity; Grade 3 or higher phosphorous toxicity; Grade 2, 3, or 4 laboratory adverse events; or Grade 2, 3, or 4 clinical adverse events; or HIV seroconversion [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
  

• Hepatitis flares among hepatitis B virus (HBV) infected persons during and after chemoprophylaxis [ Time Frame: At 42 months ] [ Designated as safety issue: Yes ]
  
• Changes in bone mineral density, body fat distribution, or fasting triglyceride and cholesterol levels [ Time Frame: At 42 months ] [ Designated as safety issue: Yes ]
  
• Among HIV infected participants: viral load, drug resistance, and CD4 count [ Time Frame: At 42 months ] [ Designated as safety issue: Yes ]
  
• Proportion of missed doses by pill count and by estimate during CASI interview [ Time Frame: At 36 months ] [ Designated as safety issue: No ]
  
• Risk behavior, including condom use before, during, and after use of study medication [ Time Frame: At 42 months ] [ Designated as safety issue: Yes ]
  
• Prevalence of sexually transmitted infections (STIs) before, during, and after use of study medication [ Time Frame: At 42 months ] [ Designated as safety issue: Yes ]
  
• Clinical or laboratory adverse events [ Time Frame: At 42 months ] [ Designated as safety issue: Yes ]
  

The Joint United Nations Programme on AIDS estimates that 14,000 persons are newly infected with HIV every day worldwide; one half of these infections occur in people between the ages of 15 and 24. New infections occur despite widespread awareness of the modes of HIV transmission and the protection afforded by condom use. Effective interventions for HIV prevention are urgently needed. This study will evaluate the safety and efficacy of chemoprophylaxis for HIV prevention in men who have sex with men (MSM) who are at high risk for HIV infection despite using condoms, receiving HIV counseling, and receiving treatment for STIs, particularly hepatitis B virus (HBV) infection. Daily FTC/TDF has been selected for evaluation because it has a well-established safety record in previous studies and was demonstrated to be effective for HIV prevention in primate models. These medications have long half-lives that allow daily dosing and do not have known interactions with hormonal contraception, methadone, or tuberculosis therapies.

Study participants will have variable follow up on study drug, which will be initiated within 4 weeks of their screening visit. On study drug follow-up may be as short as 48 weeks or as long as 144 weeks. Participants will be followed on study drug until the last enrolled participant has completed 48 weeks of on study drug follow-up. All participants will be followed for at least 8 weeks after stopping study drug. HBsAg reactive participants will be followed for hepatic flares for 16 additional weeks for a total of 24 weeks after stopping study drug. If enrolled in the optional substudy of bone mineral density, fat distribution, and fasting lipids, the participant will be asked to return for one additional visit 24 weeks after stopping study drug. Participants who HIV seroconvert during their participation in the study will also be followed until the end of on study drug follow up, and for at least 24 weeks after study participants stop taking the study drug.

All study visits will be at 4 week intervals. At study entry, high risk, HIV uninfected MSM will be randomly assigned to receive either daily FTC/TDF or placebo, in addition to standard HIV counseling, condoms, and STI management. The study will closely monitor biological and behavioral safety, including careful analysis of drug resistance, kidney and liver function, and risk behavior.

At the screening visit, participants will undergo HIV antibody and HBV testing, a medical history, a physical exam, blood and urine collection, risk behavior assessment, and STI testing. At study entry, participants will be given study medication; tested for HCV; and offered the HBV vaccine, if applicable. At all study visits, there will be HIV antibody testing, pill counts, adherence checks, study medication distribution, HIV counseling, and condom distribution. Blood collection will occur on selected visits, along with STI testing and treatment if needed. Testing and treatment of STIs will be provided at no cost to the participant.

All study participants will be encouraged to join a substudy that will assess interactions between HBV infection, bone mineral density and fat distribution, and immune function. If enrolled in the substudy, the participant will be asked to return for one additional visit 24 weeks after stopping the study medication. All participants in the substudy will undergo dual energy x-ray absorptiometry (DEXA) scans, and HIV infected participants will undergo additional blood collection.